Abstract A03: Analyses of a prostate cancer patient-derived xenografts series, a resource for translational research

• Published in: Clinical cancer research 2016-08, Vol.22 (16_Supplement), p.A03-A03
• Main Authors: Palanisamy, Nallasivam, Yang, Jun, Wan, Xinhai, Tapia, Elsa M. li Ning, Araujo, John C., Efstathiou, Eleni, Labanca, Estefania, Pisters, Louis, Aparicio, Ana, Bhalla, Ritu, Tomlins, Scott, Kunju, Lakshmi P., Chinnaiyan, Arul, Logothetis, Christopher J., Troncoso, Patricia, Navone, Nora M.
• Format: Article
• Language: English
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1557-3265.PDX16-A03

Patients with metastatic prostate cancer (PCa) have effective therapy options, but none of them are curative. Thus, their mortality rates are persistently high. Essential to furthering our progress in PCa research and therapy development is a spectrum of models that reflect the heterogeneity of the disease at each tumor site as well as the different histological variants of PCa (e.g., adenocarcinoma, small cell carcinoma). To address this challenge, we developed a strategy to establish PCa patient-derived xenografts (PDXs), using PCa tissue specimens taken from PCa sites demonstrating clinical progression. This approach provided a diverse repository of PDXs that can be linked prospectively with clinical progression and led to the identification of clinically relevant therapy targets and have proven valuable for testing drugs. We studied the first 50 PDXs developed under our program to a) define the histopathological features of paired human PCa and corresponding PDXs applying the clinically defined morphological characterization groupings of human cancer to the PDX tumors; b) assess the expression of genes known to play roles in PCa pathogenesis (e.g., androgen receptor, PTEN, ETS gene fusions) in PDXs and the human tumors of origin using immunohistochemistry and fluorescence in situ hybridization and c) perform array comparative genomic hybridization to 42 PDXs. We found that the histopathological and molecular pattern of these PDXs maintain the fidelity with the human tumor of origin. Furthermore, of the 50 cases studied, 32 (64%) were adenocarcinomas, and 16 (32%) were small cell carcinomas, poorly differentiated neuroendocrine carcinomas or mixed adenocarcinoma/ small cell carcinomas. In our cohort, we also have one sarcomatoid tumor and one ductal adenocarcinoma. Of the 32 adenocarcinomas in this cohort, 26 were AR-positive (81%), and 11 of the 27 AR-positive adenocarcinomas (41%) had aberrant expression of genes frequently involved in recurrent rearrangement (e.g., ERG, ETV1, ETV5). Also, SCCs and poorly differentiated neuroendocrine carcinomas did not express AR and were negative for ERG. This distribution recapitulates that of human PCa in the general population. Comparative genomic hybridization demonstrated gains and losses previously reported in PCa with a defined cluster of genomic aberrations. Significant differences in oncogenic pathways activation in pairs of PDXs derived from different areas of the same tumor suggesting divergent cellular p